Nociceptin/orphanin FQ (N/OFQ) is an endogenous opioid-like peptide that produces marked effects on cardiovascular (hypotension, bradycardia, sympathoinhibition) and renal excretory (water diuresis) function in animals. Using selective ligands for the N/OFQ peptide receptor (NOP), we have obtained evidence that there exist separate pathways in the brain and periphery by which N/OFQ affects cardiovascular and renal function. As proposed in this application, the development of new ligands (peptide and non-peptide) selective for the NOP receptor, a pertussis toxin-sensitive G-protein receptor, will provide the basic pharmacological tools necessary to systematically study these tissue/system specific pathways. The hypothesis to be tested is that there exist separate central and peripheral NOP receptor pathways that affect cardiovascular and renal function, and that selective activation of the peripheral NOP receptor pathway with novel peptide and non-peptide ligands can evoke a free-water diuresis devoid of adverse cardiovascular/CNS effects. The investigations proposed in this amended application will test this hypothesis using a multidisciplinary approach that can be successfully achieved by the collaborative efforts of two established investigators in the N/OFQ research field, these being the P.I., and Dr. Domenico Regoli. This will entail the synthesis of novel NOP receptor ligands using peptide and non-peptide chemistry, which will be used to elucidate the biological actions, tissue distribution and signal transduction pathways of N/OFQ and NOP receptor ligands in the brain, periphery and kidneys. These studies will employ molecular, cellular and classical pharmacological approaches involving isolated organs, tissues and whole animals; and in vivo analysis of the cardiovascular and renal responses produced by these novel NOP receptor ligands. The use of genetically modified transgenic NOP receptor knockout mice (whole animal/tissue) will provide an innovative approach to understand the effects of N/OFQ and NOP ligands at each site. The pharmacological evaluation of N/OFQ and NOP receptor ligands in different in vitro bioassays and cell culture will explore the pharmacology of the NOP receptor system and the underlying signaling pathways by which NOP receptor ligands elicit diverse cardiovascular and renal responses. Finally, the potential for novel peripherally acting NOP ligands to produce a therapeutic water diuresis in states of vasopressin excess will be explored. It is anticipated that work in this area will provide new strategies for the treatment of different pathological states associated with fluid retention and/or hyponatremia/hypokalemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL071212-04S2
Application #
7669046
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Barouch, Winifred
Project Start
2003-08-01
Project End
2009-07-31
Budget Start
2008-08-15
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$355,000
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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Krowicki, Zbigniew K; Kapusta, Daniel R (2011) Microinjection of glycine into the hypothalamic paraventricular nucleus produces diuresis, natriuresis, and inhibition of central sympathetic outflow. J Pharmacol Exp Ther 337:247-55
Wainford, Richard D; Kapusta, Daniel R (2010) Hypothalamic paraventricular nucleus G alpha q subunit protein pathways mediate vasopressin dysregulation and fluid retention in salt-sensitive rats. Endocrinology 151:5403-14
Jenkins, Meagan A; Christel, Carl J; Jiao, Yuxia et al. (2010) Ca2+-dependent facilitation of Cav1.3 Ca2+ channels by densin and Ca2+/calmodulin-dependent protein kinase II. J Neurosci 30:5125-35
Wainford, Richard D; Kapusta, Daniel R (2009) Chronic high-NaCl intake prolongs the cardiorenal responses to central N/OFQ and produces regional changes in the endogenous brain NOP receptor system. Am J Physiol Regul Integr Comp Physiol 296:R280-8
Guggilam, Anuradha; Patel, Kaushik P; Haque, Masudul et al. (2008) Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus. Eur J Heart Fail 10:625-34
Wainford, Richard D; Kurtz, Kristine; Kapusta, Daniel R (2008) Central G-alpha subunit protein-mediated control of cardiovascular function, urine output, and vasopressin secretion in conscious Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 295:R535-42
Burmeister, Melissa A; Ansonoff, Michael A; Pintar, John E et al. (2008) Nociceptin/orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice. J Pharmacol Exp Ther 326:897-904
Rizzi, Anna; Spagnolo, Barbara; Wainford, Richard D et al. (2007) In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor. Peptides 28:1240-51
Spagnolo, Barbara; Carra, Giacomo; Fantin, Martina et al. (2007) Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vitro studies. J Pharmacol Exp Ther 321:961-7

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